Project Summary/Abstract: Objectives: Chronic inflammation leads to numerous long-term health consequences including bone decay which often leads to fracture. Fractures have serious health consequences including lengthy rehabilitation and the most serious, hip fractures, may cause prolonged or permanent disability and almost always require hospitalization and major surgery. A recent retrospective, secondary analysis of National Veterans Health Administration Medicare beneficiaries concluded that one in three elderly male veterans who sustain a hip fracture die within one year. Another retrospective study of 41,331 veterans determined that approximately 18.3% of hip fracture patients were readmitted within 30 days and of those 48.5% died within one year. Therefore, prevention of fractures would represent a significant health intervention, improving longevity as well as quality of life in the veteran population. Nutritional intervention as a means to modulate health and disease represents a promising area of opportunity to improve health although sufficient data does not currently exist to optimally take advantage of this strategy. We have identified inorganic phosphate that is consumed in great excess by Americans as a nutritional element that strongly influences bone quality. The goals of this study are to further investigate the value on controlling phosphate intake for the improvement of bone quality and reduction of inflammation. Research Plan: Our published and preliminary studies have determined that consumption of high levels of dietary phosphate leads to increased inflammation, including increases in Th17 cells and osteopontin and TNF positive T cells as well as increased inflammatory serum cytokines such as TNF, IL-21 and IL-22 and ultimately bone loss in mice. Further, the reduction of dietary phosphate consumption leads to improvement in bone induces and a reduction in inflammatory cytokines suggesting a novel strategy to improve bone mass in aging individuals. This proposal will test the hypothesis that a reduced Pi diet mitigates, prevents, or reverses age associated inflammation and subsequent bone loss through a mechanism involving Pi stimulation of T cells to produce OPN, leading to an increase in Th17 cells. Methods: To test this hypothesis we will investigate whether high dietary Pi intake induces bone loss directly through T cells by conditionally silencing the Pi-transporter, Slc20a1 in T cells. We will determine if T cell production of IL-17 is required for high Pi diet to cause bone loss using transgenic mice for the IL-17 receptor and neutralizing antibody. Further, we will determine if OPN is required for high Pi and aging induced bone loss as an activator of T cells and/or a T cell secreted effector molecule stimulating the differentiation of the pro- osteoclastic Th17 cells using the OPN null mouse and adoptive transfer. We will investigate whether a reduced Pi intake mitigates the increase in Th17 and age dependent bone loss and if a reduced Pi diet later in life reverses bone loss. Furthermore, whether manipulating dietary Pi can enhance fracture healing. Clinical Relevance: Prevention of fractures will greatly reduce both the personal and financial burden to veterans relative to post-fracture treatment. Additionally, the ability to reduce inflammation could have wide ranging health benefits particularly in an aging population. These studies will be the first to investigate the effect of the common nutritional element, Pi, particularly relevant to the dietary habits of veterans and Americans in general, on immune system function and bone disease. Results will unveil new clinically relevant prevention strategies and may have consequences on health and disease well beyond bone metabolism.